Evidence suggests that a complex hypothalamic neural circuitry may control pituitary LH secretion. We propose to test the hypothesis that an array of locally derived inhibitory and excitatory regulatory neuropeptides may participate in sustaining episodic LHRH-LH secretion in male rats. Further, inappropriate function of one or more of these neurochemical signals on a long-term basis, as in hyperprolactinemia or during aging, may result in subnormal function of the LHRH-LH axis. In this context, our focus will be on two inhibitory (endogenous opioid peptides (EOP), and Neuropeptide K) and two excitatory (Neuropeptide Y and Galanin) neuropeptides. Experiments are designed to decipher how they may act to modify the LHRH-LH axis, whether activation of corticotropin releasing hormone or EOP is involved and to delineate the relationship between gonadal steroids and the output of these neuropeptides. For EOP involvement, we will extend our ongoing studies to identify the factors responsible for imparting increased feedback sensitivity towards gonadal steroids. For the other three peptides, newer studies are proposed in young, old and hyperprl rats to assess their effects on hypothalamic LHRH output, on pituitary LH release alone and in conjunction with LHRH, to understand the effects of castration and gonadal steroid replacement (time course, strength and duration characteristics) on the output of each of these peptides and to identify the hypothalamic site(s) most affected by these manipulations. We will employ cellular and molecular biology techniques combined with RIA for measurement of LH and neuropeptides in samples obtained via chronic intrajugular cannulae, push-pull cannula technique and in vitro hypothalamic and dispersed pituitary cell perfusions. It is hoped that the outcome of these studies will enhance our understanding of the mode of action, physiological arrangements and interactions with gonadal steroids of these neuropeptides within the hypothalamic circuitry that controls the LHRH-LH axis in young, hyperprl and aged rats.